For over 40 years, fluorouracil has been the only drug registered for the treatment of metastatic colorectal cancer. During the past 5 years, combination chemotherapy regimens including either irinotecan or oxaliplatin have proven to be superior to fluorouracil monotherapy in randomized clinical trials, in terms of response rate, progression-free survival and overall survival. Both doublets demonstrated similar efficacy, therefore either combination can be considered standard first-line treatment for metastatic colorectal cancer. Recently, a new orally active fluorouracil analog, capecitabine, and two targeted biological agents, cetuximab and bevacizumab, have been added to the armamentarium of drugs active against metastatic colorectal cancer, thus making the scenario more complex. Moreover, ongoing clinical trials are currently testing new promising molecularly targeted agents. Thus, we are facing a new era in which the rapid clinical development of novel agents is outpacing the ability to perform Phase III clinical trials. At present, there is no single standard treatment suitable for all patients. However, general principles of management can be derived from the available clinical data in order to guide the therapeutic choice and individualize treatment.